Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy

ABSTRACT

The present invention provides compositions and methods for administering oxybutynin while minimizing the incidence and or severity of adverse drug experiences associated with oxybutynin therapy. In one aspect, these compositions and methods provide a lower plasma concentration of oxybutynin metabolites, such as N-desethyloxybutynin, which is presumed to be contributing at least in part to some of the adverse drug experiences, while maintaining sufficient oxybutynin plasma concentration to benefit a subject with oxybutynin therapy. The invention also provides isomers of oxybutynin and its metabolites that meet these characteristics of minimized incidence and/or severity of adverse drug experiences, and maintenance of beneficial and effective therapy for overactive bladder.

PRIORITY DATA

This patent application is a continuation of U.S. patent applicationSer. No. 10/098,752, filed Mar. 15, 2002, which is a continuation ofU.S. patent application Ser. No. 09/559,711, filed Apr. 26, 2000, eachof which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for minimizingadverse drug experiences associated with oxybutynin therapy.Accordingly, this invention covers the fields of pharmaceuticalsciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION

Oral oxybutynin is currently used for treating various forms ofoveractive bladder and urinary incontinence. Particularly, oxybutynineffectively treats neurogenically caused bladder disorders. Relief fromsuch disorders is attributed to the anticholinergic and antispasmodicaction which oxybutynin imparts to the parasympathetic nervous systemand the urinary bladder detrusor muscle.

It is generally believed that, while this anticholinergic activitycontributes to oxybutynin's clinical usefulness, it also contributes tocertain uncomfortable adverse drug experiences such as dry mouth,dizziness, blurred vision, and constipation. More specifically, theseexperiences have been generally attributed to the presence and amount ofactive metabolites of oxybutynin, for example, N-desethyloxybutynin. Theabove-referenced adverse drug experiences are observed in a majority ofpatients using current oxybutynin formulations. In some cases, theseadverse experiences are severe enough to persuade the patient todiscontinue treatment.

In view of the foregoing, compositions and methods for administeringoxybutynin to help minimize the incidence and/or severity of theabove-described adverse drug experiences are extremely desirable.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a method of minimizing anadverse drug experience associated with oxybutynin therapy whichcomprises the step of administering a pharmaceutical compositioncomprising oxybutynin to a subject such that the ratio of area under theplasma concentration-time curve (AUC) of oxybutynin to an oxybutyninmetabolite is about 0.5:1 to about 5:1. The adverse drug experience maybe any adverse experience resulting from administration of oxybutynin,for example, anticholinergic, and/or antimuscarinic in nature.

Specific examples of known oxybutynin adverse experiences include butare not limited to: gastrointestinal/genitourinary experiences, nervoussystem experiences, cardiovascular experiences, dermatologicalexperiences, and opthalmic experiences, among others.

Delivery formulations useful in conjunction with the method of thepresent invention include but are not limited to: oral, parenteral,transdermal, inhalant, or implantable formulations. In one aspect of theinvention, the delivery formulation is a transdermal deliveryformulation.

Oxybutynin has a chiral molecular center, leading to the presence of(R)- and (S)-isomers. When metabolized, oxybutynin gives rise tometabolites such as N-desethyloxybutynin, which may also be present as(R)- and (S)-isomers or a combination thereof. The method of the presentinvention specifically encompasses each isomer for both oxybutynin andits any corresponding metabolites. For example, in one aspect, the meanplasma AUC ratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1. Inanother aspect, the mean AUC ratio of (R)-N-desethyloxybutynin to(R)-oxybutynin is from about 0.4:1 to about 1.6:1. In one aspect, thismean AUC ratio may be about 1:1. In another aspect, the mean AUC ratioof (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about0.5:1 to about 1.3:1. For example, this mean AUC ratio may be about0.9:1. In another aspect, the metabolite may have a mean peak plasmaconcentration of less than about 8 ng/ml.

A pharmaceutical composition for administering oxybutynin to a subjectis also provided, comprising oxybutynin that provides an AUC ratio ofoxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1.

Examples of suitable dosage formulations for the composition include:oral, parenteral, transdermal, inhalant, or implantable typecompositions. In one aspect, the composition is a transdermalcomposition.

The compositions may contain oxybutynin in its various (R)- and(S)-isomeric forms, or mixtures thereof. Further, the compositions mayinclude as well as (R) and (S)-isomeric forms oxybutynin metabolites. Inone aspect of the present invention, the composition results in an(R)-oxybutynin to (S)-oxybutynin mean AUC ratio of about 0.7:1. Inanother aspect, the composition of the present invention results in an(R)-N-desethyloxybutynin to (R)-oxybutynin mean AUC ratio of from about0.4:1 to about 1.6:1. In an additional aspect, this ratio is about 1:1.In another aspect, the (R)-N-desethyloxybutynin to(S)-N-desethyloxybutynin mean AUC ratio may be from about 0.5:1 to about1.3:1. In one aspect, the ratio is about 0.9:1. In yet another aspect,the mean peak metabolite plasma concentration may be less than about 8ng/ml.

The composition of the present invention may include a pharmaceuticallyacceptable carrier, and other ingredients as dictated by the particularneeds of the specific dosage formulation. Such ingredients are wellknown to those skilled in the art. See for example, Gennaro, A.Remington: The Science and Practice of Pharmacy 19^(th) ed. (1995),which is incorporated by reference in its entirety. For example, atransdermal formulation include, but not limited to, permeationenhancers, anti-irritants, adhesion adjusters, and combinations thereof.

There has thus been outlined, rather broadly, the more importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated. Other features of the presentinvention will become clearer from the following detailed description ofthe invention, taken with the accompanying drawings and claims, or maybe learned by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured following a 5 mgoxybutynin immediate-release oral dosage formulation.

FIG. 2 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 24 hours therefrom.

FIG. 3 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 96 hours therefrom, and for anadditional 12 hours following the removal of the transdermal system at96 hours.

FIG. 4 is a graphical representation of the results of treating asubject with overactive bladder with transdermal administration ofoxybutynin in accordance with the present invention, as compared totreatment with a 5 mg immediate-release oxybutynin oral tablet byrecording the number of episodes of urinary incontinence.

FIG. 5 is a graphical representation of the anticholinergic adverseexperiences reported by subjects receiving treatment for overactivebladder with a transdermal administration of oxybutynin in accordancewith the present invention, as compared to treatment with a 5 mgoxybutynin immediate-release oral tablet.

FIG. 6 is a graphical representation of the plasma concentrationsproduced for the (R) and (S) isomers of both oxybutynin andN-desethyloxybutynin upon administering a 5 mg immediate-release oraltablet.

FIG. 7 is a graphical representation of the plasma concentrations of (R)and (S) isomers for both oxybutynin and N-desethyloxybutynin achieved bytransdermal administration in accordance with the present invention.

DETAILED DESCRIPTION

Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

The singular forms “a,” “an,” and, “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“an adhesive” includes reference to one or more of such adhesives, andreference to “an excipient” includes reference to one or more of suchexcipients.

“Oxybutynin” refers to the compound known by several IUPAC names such asα-Cyclohexyl-α-hydroxy-benzenacetic acid 4-(diethylamino)-2-butynylester; α-phenylcyclohexaneglycolic acid 4-(diethylamino)-2-butynylester; and 4-diethylamino-2-butynylphenylcyclohexylglycolate. Theoxybutynin acid addition salt, oxybutynin HCl, is listed in the MerckIndex, entry no., 7089, at page 1193, 12th ed., (1996). “Oxybutynin” asused herein includes oxybutynin free base, its acid addition salts suchas oxybutynin HCl, their analogs and related compounds, isomers,polymorphs, and prodrugs thereof. It is generally known that oxybutyninmay exist in one or both of its isomeric forms, known as the (R)- and(S)-isomers, or a mixture of these two isomers. These isomeric forms andtheir mixtures are within the scope of this invention.

“Administration,” and “administering” refer to the manner in which adrug is presented to a subject. Administration can be accomplished byvarious art-known routes such as oral, parenteral, transdermal,inhalation, implantation, etc. Thus, an oral administration can beachieved by swallowing, chewing, sucking of an oral dosage formcomprising the drug. Parenteral administration can be achieved byinjecting a drug composition intravenously, intra-arterially,intramuscularly, intrathecally, or subcutaneously, etc. Transdermaladministration can be accomplished by applying, pasting, rolling,attaching, pouring, pressing, rubbing, etc., of a transdermalpreparation onto a skin surface. These and additional methods ofadministration are well-known in the art.

The term “non-oral administration” represents any method ofadministration in which a drug composition is not provided in a solid orliquid oral dosage form, wherein such solid or liquid oral dosage formis traditionally intended to substantially release and or deliver thedrug in the gastrointestinal tract beyond the mouth and/or buccalcavity. Such solid dosage forms include conventional tablets, capsules,caplets, etc., which do not substantially release the drug in the mouthor in the oral cavity.

It is appreciated that many oral liquid dosage forms such as solutions,suspensions, emulsions, etc., and some oral solid dosage forms mayrelease some of the drug in the mouth or in the oral cavity during theswallowing of these formulations. However, due to their very shorttransit time through the mouth and the oral cavities, the release ofdrug from these formulations in the mouth or the oral cavity isconsidered de minimus or insubstantial. Thus, buccal patches, adhesivefilms, sublingual tablets, and lozenges that are designed to release thedrug in the mouth are non-oral compositions for the present purposes.

In addition, it is understood that the term “non-oral” includesparenteral, transdermal, inhalation, implant, and vaginal or rectalformulations and administrations. Further, implant formulations are tobe included in the term “non-oral,” regardless of the physical locationof implantation. Particularly, implantation formulations are known whichare specifically designed for implantation and retention in thegastrointestinal tract. Such implants are also considered to be non-oraldelivery formulations, and therefore are encompassed by the term“non-oral.”

The term “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and other animals such as horses,pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, the terms “formulation” and “composition” are usedinterchangeably. The terms “drug” and “pharmaceutical” are also usedinterchangeably to refer to a pharmacologically active substance orcomposition. These terms of art are well-known in the pharmaceutical andmedicinal arts.

The term “transdermal” refers to the route of administration thatfacilitates transfer of a drug through a skin surface wherein atransdermal composition is administered to the skin surface.

The term “skin” or “skin surface” is meant to include not only the outerskin of a subject comprising one or more of epidermal layers, but alsoto include mucosal surfaces to which a drug composition may beadministered. Examples of mucosal surfaces include the mucosa of therespiratory (including nasal and pulmonary), oral (mouth and buccal),vaginal, and rectal cavities. Hence the terms “transdermal” mayencompass “transmucosal” as well.

The terms “enhancement”, or “permeation enhancement,” mean an increasein the permeability of the skin, to a drug, so as to increase the rateat which the drug permeates through the skin. Thus, “permeationenhancer” or simply “enhancer” refers to an agent, or mixture of agentsthat achieves such permeation enhancement.

An “effective amount” of an enhancer means an amount effective toincrease penetration of a drug through the skin, to a selected degree.Methods for assaying the characteristics of permeation enhancers arewell-known in the art. See, for example, Merritt et al., DiffusionApparatus for Skin Penetration, J. of Controlled Release 61 (1984),incorporated herein by reference in its entirety. By “effective amount”or “therapeutically effective amount,” or similar terms is meant anon-toxic but sufficient amount of a drug, to achieve therapeuticresults in treating a condition for which the drug is known to beeffective. The determination of an effective amount is well-within theordinary skill in the art of pharmaceutical and medical sciences. Seefor example, Curtis L. Meinert & Susan Tonascia, Clinical Trials:Design, Conduct, and Analysis, Monographs in Epidemiology andBiostatistics, vol. 8 (1986).

By the term “mean,” “mathematical mean,” “average,” or similar termswhen used in conjunction with the recitation of a number, or numbers,means the sum of all the individual observations or items of a sampledivided by the number of items in the sample.

By the term “matrix”, “matrix system”, or “matrix patch” is meant acomposition comprising an effective amount of a drug dissolved ordispersed in a polymeric phase, which may also contain otheringredients, such as a permeation enhancer and other optionalingredients. This definition is meant to include embodiments whereinsuch polymeric phase is laminated to a pressure sensitive adhesive orused within an overlay adhesive.

A matrix system may also comprise an adhesive layer having animpermeable film backing attached onto the distal surface thereof and,before transdermal application, a release liner on the proximal surfaceof the adhesive. The film backing protects the polymeric phase of thematrix patch and prevents release of the drug and/or optionalingredients to the environment. The release liner functions similarly tothe impermeable backing, but is removed from the matrix patch prior toapplication of the patch to the skin as defined above. Matrix patcheswith the above-described general characteristics are known in the art oftransdermal delivery. See, for example, U.S. Pat. Nos. 5,985,317,5,783,208, 5,626,866, 5,227,169, which are incorporated by reference intheir entirety.

“Topical formulation” means a composition in which the drug may beplaced for direct application to a skin surface and from which aneffective amount of the drug is released.

“Adverse drug experience” refers to any adverse event associated withthe use of a drug in a subject, including the following: an adverseevent occurring in the course of the use of a drug product inprofessional practice; an adverse event occurring from drug overdosewhether accidental or intentional; an adverse event occurring from drugabuse; an adverse event occurring from drug withdrawal; and any failureof expected pharmacological action. The adverse drug experience may leadto a substantial disruption of a person's ability to conduct normal lifefunctions. In some instances, the adverse drug experience may be seriousor life threatening.

While some of the adverse drug experiences may be expected, in someinstances, such experiences may be unexpected. “Unexpected,” refers toan adverse drug experience that has not been previously catalogued by aresponsible governmental agency (such as the Food and DrugAdministration of the United States) and or not provided in the currentlabeling for the drug product.

The unexpected adverse experiences may include events that may besymptomatically and pathophysiologically related to a known event, butdiffer from the event because of greater severity or specificity. Forexample, under this definition, hepatic necrosis would be unexpected (byvirtue of greater severity) if the known event is elevated hepaticenzymes or hepatitis. Similarly, cerebral thromboembolism and cerebralvasculitis would be unexpected (by virtue of greater specificity) if theknown event is cerebral vascular accidents. For a more comprehensivedefinition and description of adverse drug experience, see 21 C.F.R. §314.80, which is incorporated by reference in its entirety.

The majority of the adverse experiences associated with oxybutynintherapy may be categorized as anticholinergic, and/or antimuscarinic.Certain adverse experiences associated with oxybutynin have beencategorized in the Physician's Desk Reference as cardiovascularexperiences, gastrointestinal/genitourinary experiences, dermatologicexperiences, nervous system experiences, and opthalmic experiences,among others.

Examples of cardiovascular adverse experiences include but are notlimited to: palpitations, tachycardia, vasodilation, and combinationsthereof. Examples of dermatologic adverse experiences include but arenot limited to: decreased sweating, rashes, and combinations thereof.Examples of gastrointestinal/genitourinary adverse experiences includebut are not limited to: constipation, decreased gastrointestinalmotility, dry mouth, nausea, urinary hesitance and retention, andcombinations thereof. Examples of nervous system adverse experiencesinclude but are not limited to: asthenia, dizziness, drowsiness,hallucinations, insomnia, restlessness, and combinations thereof.Examples of opthalmic adverse experiences include but are not limitedto: amblyopia, cycloplegia, decreased lacrimation, mydriasis, andcombinations thereof. Examples of other adverse experiences include butare not limited to: impotence and suppression of lactation. A morecomprehensive listing of adverse experiences my be found in the labelingof the oxybutynin formulations as provided by the regulatory agencies.

The term “minimize” and its grammatical equivalents refer to a reductionin the frequency and or severity of one or more adverse drug experiencesin a given subject or subject population. It is appreciated that thesubject population may be of necessity much smaller in size than thegeneral population that may be exposed to the drug and/or its adverseexperiences.

It is also appreciated that the results obtained from methods fordetermining the reduction in the frequency and/or severity of adversedrug experiences may be subject to variables such as intra-subject andinter-subject factors. However, it is also appreciated that certainscientifically accepted methods can be used to conduct the studies andthat the results from such studies are statistically reliable. Suchmethods and interpretation of the results from such methods arewell-known in the art. See, for example, Robert R. Sokal & F. JamesRohlf, Biometry: The Principles and Practice of Statistics in BiologicalResearch, 2^(nd) ed. (1969), which is incorporated by reference in itsentirety.

The phrase “area under the curve”, “area under the plasmaconcentration-time curve,” or similar terms are well known in thepharmaceutical arts. These values are calculated by plotting a graphwith data from plasma concentration of a given drug or its metabolitesas a function of time, with the X-axis generally representing time andthe Y-axis generally representing plasma concentration. The area underthe line formed by joining the various data points is then integratedinto a numerical value. See for example, Milo Gibaldi & Donald Perrier,PharmacoKinetics, 2^(nd) ed. (1982). The AUC multiplied by the clearanceor total body clearance (CL), of the substance being measured, thusprovides an estimate of the total amount, or dose, of the substancebeing measured (the drug or one or more of its metabolites). Plasmaconcentrations, AUC, and CL may be subject to inter- and intra-subjectvariation due to physiological and/or environment factors present inindividual subjects during the administration of medicinal agents, suchas oxybutynin, in various formulation and/or compositions. Therefore,individual and mean values may be subject to variability, however, thegeneral trends and relationships are preserved and reproducible.

Concentrations, amounts, solubilities, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited.

For example, a concentration range of 0.1 to 5 ng/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.1 ng/ml and 5 ng/ml, but also to include individualconcentrations such as 0.2 ng/ml, 0.7 ng/ml, 1.0 ng/ml, 2.2 ng/ml, 3.6ng/ml, 4.2 ng/ml, and sub-ranges such as 0.3-2.5 ng/ml, 1.8-3.2 ng/ml,2.6-4.9 ng/ml, etc. This interpretation should apply regardless of thebreadth of the range or the characteristic being described.

The Invention

As described above, the present invention provides compositions andmethods for administering oxybutynin. These compositions and methods areshown to have minimized the incidence and/or severity of an adverseexperience associated with oxybutynin administration, while providingsufficient oxybutynin to impart a therapeutic benefit. Without intendingto be bound to any specific theory, it is believed that the minimizationof adverse experiences is due in part to the reduction in plasmaconcentration of metabolites of oxybutynin such as N-desethyloxybutyninby the present compositions and methods when compared to conventionaloral administration. The phrase “conventional oral administration” ismeant to include the oral formulations as defined supra, and includesfor example, an immediate-release or sustained-release oral tabletcomprising oxybutynin. One such conventional oral formulation isavailable as a 5 mg immediate-release oral tablet.

1) The Pharmacokinetic Aspects Associated with Total Drug and MetabolitePlasma Concentrations

The desired pharmacokinetic attributes such as reduced plasmaconcentrations of oxybutynin metabolites may be achieved by, interalia: 1) reducing the amount of oxybutynin administered, 2) reducing therate at which oxybutynin becomes available for metabolism by the body,and/or 3) avoiding or minimizing first-pass hepatic and/or intestinalmetabolism of oxybutynin. Using a non-oral route of administration isone way to achieve one or more of these objectives. Alternatively, anoral dosage form could be designed to mimic a non-oral administration toachieve the plasma concentrations and other pharmacokinetic datadescribed herein.

A clinical study has been performed to demonstrate one embodiment of thepresent invention. A cross-over clinical study in 16 healthy volunteerswas conducted to compare plasma concentrations and pharmacokinetics ofoxybutynin and one of its metabolites, N-desethyloxybutynin, and theirrespective (R)- and (S)-enantiomeric components.

Conventional oral dosage forms of oxybutynin, such as the 5 mgoxybutynin tablet used in the present study produce significantly higherplasma concentrations of oxybutynin metabolites such asN-desethyloxybutynin as compared to the parent drug. (See FIG. 1). Themean AUC ratio of metabolite to oxybutynin concentration is about 10:1in the majority of cases, and is generally greater than about 5:1.

In contrast, when oxybutynin is administered in a non-oral, slow releasecomposition, such as the transdermal composition embodiment of thepresent invention, the mean AUC ratio of the metabolite(N-desethyloxybutynin) to oxybutynin is much lower. Generally, the meanAUC ratio of oxybutynin metabolite (N-desethyloxybutynin) to oxybutyninis less than about 2:1. Further, in the majority of instances, the ratiois less than about 1.2:1, and often, the ratio is approximately 0.9:1.(See FIG. 3).

Additionally, the mean N-desethyloxybutynin plasma concentration isgenerally less than about 8 ng/ml, and in the majority of instances isless than about 5 ng/ml. Often the mean is less than about 3 ng/ml.

2) Pharmacokinetic Aspects of Isomers

The present inventors have investigated further into the aspectsdescribed above and have discovered that the present formulations andmethods provide significantly reduced levels of particular isomers ofcertain oxybutynin metabolites and that these reduced levels ofmetabolite isomers correlate to the minimized adverse drug experiencesdescribed above.

It is generally known that oxybutynin exists as an (R)- or as an(S)-isomer or a combination thereof. Particularly, (R)-oxybutynin hasbeen thought to be the more active of the two isomers, as indicated byanimal pharmacological studies using isolated tissues. See for example,Kachur J F, Peterson J S, Carter J P, et al. J. Pharm Exper. Ther. 1988;247:867-872; see also, Noronha-Blob L, Kachur J F. J. Pharm. Exper.Ther. 1990; 256:56-567. As such, (R)-N-desethyloxybutynin, being themore active constituent of the total amount of metabolite, maycontribute more significantly to adverse drug experiences such asanticholinergic adverse effects than the lessactive(S)-N-desethyloxybutynin. See for example, U.S. Pat. No.5,677,346, which is incorporated by reference in its entirety.

Accordingly, plasma concentrations were measured for both (R)- and(S)-oxybutynin and the corresponding isomers of one of its metabolites,N-desethyloxybutynin during the clinical study mentioned above. Thetests performed revealed that the present invention results insignificantly lower (R)-N-desethyloxybutynin plasma concentrationscompared to conventional oral dosage forms and administration methods.

FIG. 6 shows the plasma concentration profile from the conventionaloxybutynin 5 mg oxybutynin oral tablet. As can be seen,(R)-N-desethyloxybutynin is present in the greatest concentration, andis several times the concentration of both (R)- and (S)-oxybutynin. Themean AUC ratio of the (R)-N-desethyloxybutynin to (R)-oxybutynin, thetwo most active isomers, following oral administration is about 17:1. Inaddition, the mean AUC ratio of (R)-N-desethyloxybutynin to(S)-N-desethyloxybutynin is about 1.5:1, and the mean AUC ratio of(R)-oxybutynin to (S)-oxybutynin is about 0.6:1. These ratios of AUCconsistently show that orally administered oxybutynin results in arelatively low amount of therapeutically active (R)-oxybutynin given thelarge total dose of racemic oxybutynin. Further, the oral dose resultsin a relatively large amount of (R)-N-desethyloxybutynin, the moietymost likely to be responsible for causing some or many of the adversedrug experiences.

In contrast, FIG. 7 shows the (R)- and (S)-isomer plasma profiles of thepresent invention which were achieved during the clinical study bynon-orally delivered oxybutynin. The mean AUC ratio of (R)-oxybutynin to(S)-oxybutynin is about 0.7:1, and the sustained plasma concentrationsof (R)-oxybutynin are similar to the peak concentrations obtainedfollowing oral administration. This comparable exposure to thetherapeutically active (R)-oxybutynin moiety is consistent with theinvention.

Thus, with transdermal administration, it has been discovered that: themean AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutynin is lowered,resulting in greatly reduced amounts of the active metabolites ofoxybutynin, while providing a therapeutically effective amount ofoxybutynin.

By comparing FIGS. 4,5, and 7, it becomes clear that the presentcompositions and methods provide an optimal ratio of plasmaconcentrations of metabolites, such as (R)-N-desethyloxybutynin, tooxybutynin, such that these methods and compositions minimize adverseexperiences associated with oxybutynin administration, as compared totraditional oral formulations, while maintaining therapeuticallysufficient concentrations of (R)-oxybutynin to provide the benefits ofoxybutynin therapy. As indicated above, these compositions and methodsoffer a significant advancement in oxybutynin therapy.

3) Therapeutic Aspects

A clinical study on the efficacy and minimization of incidence andseverity of adverse drug experiences associated with non-orallyadministered oxybutynin was conducted using 72 human subjects (patients)with overactive bladder. Approximately one-half of the patients wereadministered oxybutynin hydrochloride in an oral dosage formulation. Theremaining patients were administered oxybutynin using a non-oral routeof delivery such as a transdermal adhesive matrix patch over a period ofabout 6 weeks. The results are displayed graphically in FIGS. 4 and 5.

The non-oral, sustained-release composition of this invention wascompared for its therapeutic efficacy with the conventional 5 mg oraltablet of oxybutynin. The mean number of incontinent episodesexperienced per day as derived from a multiple-day patient urinary diarywas used as the desired therapeutic efficacy indicator. The data showthat the number of incontinent episodes for those individuals treated bythe non-oral method of the present invention is nearly identical to thenumber for those treated with the oral formulation. (See FIG. 4).

Next, the non-oral sustained-release formulation of the presentinvention was compared to the conventional immediate-release oral tabletfor the incidence and severity of adverse drug experiences. The adverseexperience of dry mouth was selected as an indicator for thisexperiment. As can be seen, only 6% of the participants who received theconventional oral oxybutynin tablet reported no dry mouth effects.Conversely, 94% of these participants reported experiencing some drymouth.

In contrast, 62% of the participants who were treated with thetransdermal adhesive matrix patch of the present invention reported nodry mouth effects. Therefore, only 38% of these participants reportedexperiencing some dry mouth, and none rated the dry mouth asintolerable.

These data show that the adverse experiences associated with oxybutyninadministration can be minimized significantly, while fully retaining thetherapeutic efficacy of oxybutynin by administering oxybutynin such thatan optimal ratio of AUC of oxybutynin metabolite to oxybutynin results.

4) Summary of Pharmacokinetic Aspects of the Invention

From the above-described pharmacokinetic data, the following aspects ofthe invention can be presented. In one aspect, the mean peak plasmaconcentration of an oxybutynin metabolite is less than about 8 ng/ml. Inanother aspect, the mean peak plasma concentration of the metabolite isfrom about 0.5 ng/ml to about 8 ng/ml; in yet another aspect, theconcentration is less than about 5 ng/ml; in yet another aspect, theconcentration is from about 1.0 ng/ml to about 3 ng/ml. In some aspects,the metabolite of oxybutynin is N-desethyloxybutynin.

In some aspects, the mean oxybutynin metabolite AUC is reduced to anamount which does not exceed the oxybutynin AUC by more than a ratio ofabout 2:1. In some aspects, the mean oxybutynin metabolite AUC isreduced to less than about 0.9:1 ng/ml.

In some aspects, the present invention provides compositions and methodsfor administering oxybutynin to a subject such that the mean AUC ratioof oxybutynin to an oxybutynin metabolite is about 0.5:1 to about 5:1.In some aspects, the ratio is from about 0.5:1 to about 4:1; in someother aspects, the ratio is from about 1:1 to 5:1; in yet other aspects,the ratio is from about 0.8:1 to about 2.5:1; in yet some other aspects,the ratio is from about 0.8:1 to about 1.5:1. In all the above aspects,the metabolite may be N-desethyloxybutynin.

Another way of characterizing the method of the present invention is byspecifying particular plasma concentrations for oxybutynin andmetabolite concentrations at certain time intervals following treatmentinitiation. Therefore, in one aspect, oxybutynin plasma concentrationsare below about 2.0 ng/ml at about 6 hours after oxybutynin treatmentinitiation. In another aspect, the metabolite plasma concentrations arealso below about 2.0 ng/ml at about 6 hours after treatment initiation.

In yet another aspect, oxybutynin and its metabolite plasmaconcentrations are below about 8 ng/ml at about 24 hours after initialoxybutynin administration. Further, mean steady state oxybutynin and itsmetabolite plasma-concentrations are below about 8 ng/ml for theduration of oxybutynin treatment.

In one aspect, the mean peak and mean AUC for (R)-N-desethyloxybutyninare about equal to or less than the mean peak, and mean AUC for(S)-N-desethyloxybutynin. In another aspect, the mean AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1. Inyet another aspect, the mean peak and mean AUC for (R)-oxybutynin areapproximately equal to (R)-N-desethyloxybutynin. In another aspect, theratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about1:1.

In an additional aspect, (R)-N-desethyloxybutynin has a mean peak plasmaconcentration of less than about 4 ng/mL. In another aspect,(R)-N-desethyloxybutynin has a mean peak plasma concentration betweenabout 0.25 to about 4 nm/ml, and about 1.5 ng/ml.

In a one aspect, (R)-N-desethyloxybutynin has a mean AUC of about 100ng×hr/ml. In another aspect, (R)-N-desethyloxybutynin has a mean AUCfrom about 30 ng×hr/ml to about 170 ng×hr/ml.

In yet another aspect, the plasma concentration of(R)-N-desethyloxybutynin is below about 1 ng/ml at about 6 hours afterinitiation of oxybutynin administration. In a further aspect, the plasmaconcentration of (R)-N-desethyloxybutynin is below about 2 ng/ml atabout 24 hours after initiation of oxybutynin administration.

Therapeutic oxybutynin plasma concentrations vary based on the severityof incontinence. Generally, therapeutic results may be obtained fromoxybutynin plasma concentrations as low as 0.5 ng/ml. Therapeutic bloodlevels may be achieved using the method of the present invention in aslittle as 3 hours after treatment initiation, with peak oxybutyninplasma concentrations being reached in about 24 hours. However, thesegeneral parameters are not limitations on the way in which the desiredplasma levels may be achieved. Different delivery methods, rates, andamounts may be used to effect the desired plasma concentrations byemploying a formulation which produces different parameters.

5) Composition Aspects

Any pharmaceutically acceptable compositions and methods foradministering such compositions may be used for achieving the desiredaspects of this invention. For example, oral and non-oral compositionsand methods of administration can be used. Non-oral compositions andmethods of administration include parenteral, implantation, inhalation,and transdermal compositions and methods.

Oral compositions and administrations can comprise of slow-releasecompositions that are designed to mimic the non-oral compositions andadministrations that are specifically disclosed herein in terms of theirpharmacokinetic attributes described above. One of ordinary skill in theart would readily understand how to formulate and administer suchslow-release oral formulations. These formulations can take the form ofa tablet, capsule, caplet, pellets, encapsulated pellets, etc., or aliquid formulation such as a solution or suspension. See, for example,U.S. Pat. No. 5,840,754, and WO 99/48494 which are incorporated byreference in their entirety.

Parenteral compositions and administrations may include intravenous,intra-arterial, intramuscular, intrathecal, subcutaneous, etc. Thesecompositions can be prepared and administered to provide slow-release ofoxybutynin to achieve the pharmacokinetic profile and therapeuticbenefits described above. One specific example of preparing adepot-formulation for parenteral use is provided herein. General methodsfor preparing sustained delivery of drugs for parenteral use comprisingmicrospheres are known in the art. See for example, U.S. Pat. Nos.5,575,987, 5,759,583, 5,028,430, 4,959,217, and 4,652,441, hich areincorporated by reference in their entirety.

Implantation is a technique that is well-established to providecontrolled release of drugs over a long period of time. Severalsubcutaneously implantable devices have been disclosed in the art. Seefor example, U.S. Pat. Nos. 5,985,305, 5,972,369, and 5,922,342, whichare incorporated by reference in their entirety. By employing thesegeneral techniques, one of ordinary skill in the art can prepare andadminister implantable oxybutynin compositions to achieve thepharmacokinetic and therapeutic benefits of this invention.

Examples of oxybutynin transdermal administration formulations includebut are not limited to: 1) topical formulations such as ointments,lotions, gels, pastes, mousses, aerosols, and skin creams; 2)transdermal patches such as adhesive matrix patches and liquid reservoirsystems. Other non-oral examples include transmucosal tablets such asbuccal, or sublingual tablets or lozenges, and suppositories.

In addition to the desired amount of oxybutynin, transdermal oxybutyninformulations may also include a permeation enhancer, or mixture ofpermeation enhancers in order to increase the permeability of the skinto oxybutynin. A comprehensive index of permeation enhancers isdisclosed by David W. Osborne and Jill J. Henke, in their internetpublication entitled Skin Penetration Enhancers Cited in the TechnicalLiterature, which may be found at the worldwide web address known as:pharmtech.com/technical/osborne/osborne.htm, which is incorporated byreference herein.

More particularly, permeation enhancers known to enhance the delivery ofoxybutynin include but are not limited to: fatty acids, fatty acidesters, fatty alcohols, fatty acid esters of lactic acid or glycolicacid, glycerol tri-, di- and monoesters, triacetin, short chainalcohols, and mixtures thereof. Specific species or combinations ofspecies may be selected from the above listed classes of compounds byone skilled in the art, in order to optimize enhancement of theparticular oxybutynin composition employed.

The transdermal formulation of the present invention may take the formof an occlusive device, such as a transdermal patch. Such a transdermalpatch may either be an adhesive matrix patch, a liquid reservoir systemtype patch, a buccal tablet, lozenge, or the like. Optional ingredientssuch as adhesives, excipients, backing films, etc, and the requiredamount of each will vary greatly depending upon the type of patchdesired, and may be determined as needed by one ordinarily skilled inthe art. Methods for preparing and administering the transdermalformulations with the above-described characteristics are known in theart. See, for example, U.S. Pat. Nos. 5,862,555, 5,762,953, and5,152,997, which are incorporated by reference in their entirety.

However, these general parameters are not limitations on the way inwhich the desired plasma levels may be achieved. Different deliverymethods, rates, and amounts may be used to effect the desired plasmalevels by employing a formulation which produces different parameters.

EXAMPLES

The following examples of non-oral delivery formulations having avariety of oxybutynin containing compositions are provided to promote amore clear understanding of the possible combinations of the presentinvention, and are in no way meant as a limitation thereon.

Materials used in the present invention were obtained from specificsources which are provided as follows. Where the materials are availablefrom a variety of commercial sources, no specific source has beenprovided. Oxybutynin free base was obtained from Ceres Chemical Co.Inc., White Plains, N.Y. (USA). The enantiomers of oxybutynin andnamely, the (R)- and (S)-isomers were obtained from Sepracor. Sepracor,Marlborough, Mass. (USA).

Example 1 Preparation of Oxybutynin Adhesive Matrix Patch

The non-oral oxybutynin delivery devices used in the clinical studyreferred to above were 13 and/or 39 cm² transdermal adhesive matrixpatches. A general method of preparing transdermal adhesive matrixpatches is described by U.S. Pat. Nos. 5,227,169, and 5,212,199, whichare incorporated by reference in their entirety. Following this generalmethod, the oxybutynin patches of this invention were prepared asfollows:

Oxybutynin free base, triacetin (Eastman Chemical Co., Kingsport, N.Y.)and 87-2888 acrylic copolymer adhesives (National Starch and ChemicalCo., Bridgewater, N.J.) were mixed into a homogenous solution and coatedat 6 mg/cm² (dried weight) onto a silicone treated polyester releaseliner (Rexham Release, Chicago, Ill.) using a two zonecoating/drying/laminating oven (Kraemer Koating, Lakewood, N.J.) toprovide a final oxybutynin adhesive matrix containing 15.4%, 9.0%, and75.6% by weight oxybutynin, triacetin and acrylic copolymer adhesive,respectively. A fifty micron thick polyethylene backing film (3M, St.Paul, Minn.) was subsequently laminated onto the dried adhesive surfaceof the oxybutynin containing adhesive matrix and the final laminatestructure was die cut to provide patches ranging in size from 13 cm² to39 cm² patches.

Example 2 Preparation of Oxybutynin Biodegradable Microsphere DepotInjection

Biodegradable microspheres for effecting a sustained-release depotinjection may be used to deliver oxybutynin in accordance with themethod of the present invention. Microspheres were prepared by thefollowing method:

12,000 molecular weight poly-d,l lactic acid (“PLA”, BirminghamPolymers, Birmingham, Ala.) was dissolved into methylene chloride at afinal concentration of 20% by weight. Oxybutynin free base was dissolvedinto the PLA solution at 4% by weight in the final solution. Awater-jacketed reaction vessel (temperature controlled at 5 degreesCelsius) equipped with a true-bore stirrer fitted with a Teflon turbineimpeller was charged with a de-ionized water containing 0.1% Tween 80.

The oxybutynin/PLA/methylene chloride solution was added drop wise intothe reaction vessel and stirred to dispense the organic polymer phasewithin the aqueous solution as fine particles. The resultant suspensionwas filtered and washed once with de-ionized water and finally dried ona roto-evaporator to removed methylene chloride. The resultantmicrospheres can be injected either intramuscularly or subcutaneously toprovide a prolonged systemic release of oxybutynin.

Example 3 Preparation of Topical Oxybutynin Formulation

Topically applied oxybutynin containing gel may be used to deliveroxybutynin in accordance with the method of the present invention. Ageneral method of preparing a topical gel is known in the art. Followingthis general method, a topical gel comprising oxybutynin was prepared asfollows:

95% ethanol (USP) was diluted with water (USP), glycerin (USP), andglycerol monooleate (Eastman Chemical, Kingsport N.Y.) to provide afinal solution at ethanol/water/glycerin/glycerol monooleate percentratios of 35/59/5/1, respectively. Oxybutynin free base was thendissolved into the above solution to a concentration of 10 mg/gram. Theresultant solution was then gelled with 1% hydroxypropyl cellulose(Aqualon, Wilmington, Del.) to provide a final oxybutynin gel. One totwo grams of the above gel is applied topically to approximately 200 cm²surface area on the chest, torso, and or arms to provide topicaladministration of oxybutynin.

Example 4 Clinical Study to the Determine the Pharmacokinetics ofOxybutynin, N-desethyloxybutynin and their Respective (R) and (S)Isomers following Oral administration of Racemic Oxybutynin inComparison to Transdermally Administered Racemic Oxybutynin

A clinical study in 16 healthy volunteers compared, in a cross-overfashion, the comparative plasma concentrations and pharmacokinetics ofoxybutynin, N-desethyloxybutynin, and their respective (R)- and(S)-enantiomeric components.

Healthy volunteers were recruited from the local population and includedmen and women ranging in age from 19 to 45 years. Following a pre-studyexamination to confirm a healthy condition in all volunteers, eachsubject participated in 2 study periods during which the testmedications, either a transdermal oxybutynin system applied for 4 daysor a single 5 mg oral immediate-release dose of oxybutynin, wereadministered. Blood samples were collected periodically throughout thestudy periods. Plasma was harvested from the samples according to astandard method. The quantities of (R) and (S) oxybutynin and (R) and(S)N-desethyloxybutynin were measured in the plasma samples through theapplication of a validated mass spectrometric method coupled with liquidchromatographic separation of the individual constituents. A PerkinElmer high performance liquid chromatographic pump was used inconjunction with a Chrom Tech AGP 150.2 chromatographic column. The massspectrometry instrument was an API 300 operated in MRM scan mode withelectrospray ionization. A linear response of the quantitation of theanalytes was confirmed with standard solutions and the performance ofthe assay was controlled using quality control samples analyzed inconjunction with the study samples. The range of linearity was 0.5 to 75ng/ml with linear correlation coefficients greater than 0.99 for allanalytes.

FIGS. 1,2,3,6, and 7 show graphical displays of these data. In FIG. 1,oxybutynin and N-desethyloxybutynin plasma concentrations are shownfollowing administration of the 5 mg immediate-release oral dosageoxybutynin hydrochloride tablets, Ditropan® Alza Corporation. Thesetablets were obtained commercially and can be obtained from variousgeneric manufacturers. Plasma concentration is indicated on the verticalaxis, and time is indicated on the horizontal axis. As can be seen, theplasma concentrations of N-desethyloxybutynin are significantly greaterthan oxybutynin plasma concentrations. The mean AUC ratio forN-desethyloxybutynin to oxybutynin is about 10:1.

FIG. 3 illustrates the plasma concentration profiles for oxybutynin andN-desethyloxybutynin during and following application of the transdermalsystem. As can be seen, the N-desethyloxybutynin plasma concentrationsfor the adhesive matrix patch embodiment, fall well within theparameters prescribed by the present invention. The mean AUC ratio forN-desethyloxybutynin to oxybutynin is about 0.9:1 and the mean plasmaconcentrations for N-desethyloxybutynin are less than about 2.5 ng/ml.

FIGS. 6 and 7 illustrate the plasma concentrations of the individualisomers of oxybutynin and N-desethyloxybutynin as measured during theclinical trial described above. As can be seen in FIG. 6, oraladministration of oxybutynin leads to relatively high concentrations of(R)-N-desethyloxybutynin. This active metabolite moiety is present inthe greatest concentration, and is several times the concentration ofboth (R) and (S) oxybutynin. The mean ratio of AUC of(R)-N-desethyloxybutynin to (R)-oxybutynin is about 17:1 and the meanAUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin isabout 1.5:1.

Following application of the transdermal oxybutynin system, the mean AUCratio of the active moieties, (R)-N-desethyloxybutynin to(R)-oxybutynin, is about 1:1, substantially lower than following oraladministration. Additionally, the mean AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1,consistent with substantially lower metabolic first pass conversion ofthe active (R)-oxybutynin to (R)-N-desethyloxybutynin. The mean AUCratio of (R)- to (S)-oxybutynin is about 0.7:1, similar to that presentfollowing oral administration.

The lower overall amount of oxybutynin delivered during transdermaldelivery of oxybutynin was estimated based on the residual amount ofoxybutynin remaining in the transdermal system after the 4-dayapplication period subtracted from the amount determined in unusedtransdermal systems. The mean amount delivered over 4 days was about 12mg or an average of about 3 mg/day. The oral dose of oxybutyninadministered in the study was 5 mg, a dose that may be administeredevery 12 hours, or two times daily, during therapeutic use of theproduct. This allows a comparison of a dose of about 5 mg every 12 hoursfor oral treatment compared to about 1.5 mg every 12 hours fortransdermal treatment.

In summary, the pharmacokinetics of transdermal, non-oral, oxybutyninadministration illustrate the aspects of the invention with regard to asustained, slower rate of administration of oxybutynin and a lower doseor overall amount of oxybutynin administered.

Example 5 Comparative Analysis of Therapeutic Efficacy and Incidence andSeverity of Anticholinergic Side Effects, Primarily Dry Mouth, ofConventional Oral Tablet Formulation and Transdermal Formulation of thePresent Invention

A clinical study of the efficacy and incidence of side effects wasconducted in 72 patients with overactive bladder. These patients wererecruited by independent clinical investigators located in variousregions of the U.S.A. Approximately half of the patients wereadministered oxybutynin hydrochloride in an immediate-release oraldosage formulation. The remaining patients were administered oxybutyninusing in each case one or more 13 cm² oxybutynin containing transdermaladhesive matrix patches. In each of these treatment groups, themedications were blinded by the concomitant administration of matchingplacebo forms of the treatments. In the case of active oral treatment,the patients applied placebo transdermal systems that contained allingredients of the active transdermal system with the exception of theactive drug oxybutynin. In like fashion, the active transdermaltreatment group received matching oral formulations without the activeoxybutynin constituent. In this study, the patients included both menand women, with the majority being women with an average age of 63-64years. All patients had a history of urinary incontinence associatedwith overactive bladder and demonstrated a mean of at least 3incontinent episodes per day during a washout period during which nomedical therapy for incontinence was used.

Therapeutic efficacy was based on the mean number of incontinentepisodes experienced per day as derived from a multiple-day patienturinary diary. The data are displayed graphically in FIG. 4.

As can be seen, the number of incontinent episodes for those individualstreated by the non-oral method of the present invention is nearlyidentical to the number for those treated with the oral formulation.This indicates clearly that the present methods and compositions providefor a therapeutically effective treatment for urinary incontinence andoveractive bladder that is comparable to the conventional oralformulation, such as a 5 mg oral oxybutynin tablet. Incidence and/orseverity of adverse drug experience was also compared between theconventional oral tablet formulation of oxybutynin administered as aboveand the transdermal formulation. Anticholinergic adverse experience,such as the incidence and severity of dry mouth, was used as anindicator of the adverse experience that can be associated with theadministration of either formulation and represents an anticholinergicside effect. The clinical study participants were asked to report thisexperience according to a standardized questionnaire. The data derivedfrom the questionnaire are displayed graphically in FIG. 5. Thepercentage of participants reporting dry mouth is indicated on thevertical axis, and the severity of the dry mouth is indicated on thehorizontal axis.

As can be seen, only 6% of the participants who received the oral formreported no dry mouth effects. Conversely, 94% of these participantsreported experiencing some dry mouth. By contrast, 62% of theparticipants who were treated with the 13 cm² transdermal adhesivematrix patches reported no dry mouth effects. Therefore, only 38% ofthese participants reported experiencing some dry mouth. Therefore, theclinical data shows that matrix patch embodiment of the method of thepresent invention, provides a treatment for overactive bladder whichachieves nearly identical therapeutic effectiveness as an oral form,while significantly minimizing the incidence and or severity of adverseexperiences associated with oxybutynin administration.

FIG. 7 shows that the (R)-N-desethyloxybutynin concentrations are lowerthan the (S)-N-desethyloxybutynin concentrations, and further, theconcentrations of (R)-oxybutynin increase slowly and are maintained atan approximately constant level throughout the patch application timeperiod. The reduced plasma concentrations of (R)-N-desethyloxybutyninappears to have contributed to the minimization of the incidence andseverity of adverse drug experiences such as dry mouth, while the plasmaconcentrations of (R)-oxybutynin retain the therapeutic effectiveness ofthe treatment, as shown by FIGS. 4 and 5.

It is to be understood that the above-described compositions and modesof application are only illustrative of preferred embodiments of thepresent invention. Numerous modifications and alternative arrangementsmay be devised by those skilled in the art without departing from thespirit and scope of the present invention and the appended claims areintended to cover such modifications and arrangements.

Thus, while the present invention has been described above withparticularity and detail in connection with what is presently deemed tobe the most practical and preferred embodiments of the invention, itwill be apparent to those of ordinary skill in the art that numerousmodifications, including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

1. A method of treating with oxybutynin a subject having overactivebladder, while minimizing an anticholinergic or antimuscarinic adversedrug experience associated with said oxybutynin treatment therapycomprising the step of: administering as a transmucosal formulation, acomposition comprising oxybutynin to a subject to provide a plasma areaunder the curve (AUC) ratio of oxybutynin to an oxybutynin metabolite offrom about 0.5:1 to about 5:1, wherein the transmucosal formulationoptionally includes a permeation enhancer.
 2. The method of claim 1,wherein the transmucosal formulation is a buccal tablet.
 3. The methodof claim 1, wherein the transmucosal formulation is a sublingual tablet.4. The method of claim 1, wherein the transmucosal formulation is anadhesive film.
 5. The method of claim 1, wherein the AUC ratio ofoxybutynin to an oxybutynin metabolite is from about 1:1 to about 5:1.6. The method of claim 1, wherein the AUC ratio of oxybutynin to anoxybutynin metabolite is from about 0.8:1 to about 1.5:1.
 7. The methodof claim 1, wherein the oxybutynin in the plasma is (R)-oxybutynin,(S)-oxybutynin, or a combination thereof.
 8. The method of claim 1,wherein the metabolite of oxybutynin is N-desethyloxybutynin.
 9. Themethod of claim 8, wherein the N-desethyloxybutynin is(R)-N-desethyloxybutynin, (S)-N-desethyloxybutynin or a combinationthereof.
 10. The method of claim 7, wherein the AUC ratio of(R)-oxybutynin to (S)-oxybutynin is about 0.7:1.
 11. The method of claim9, wherein the AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutyninis from about 0.4:1 to about 1.6:1.
 12. The method of claim 11, whereinthe AUC ratio of (R)-N-desethyloxybutynin to (R)-oxybutynin is about1:1.
 13. The method of claim 9, wherein the AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about 0.5:1to about 1.3:1.
 14. The method of claim 13, wherein the AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is about 0.9:1. 15.The method of claim 1, wherein the metabolite plasma concentrationreaches a peak plasma value of less than about 8 ng/ml.
 16. The methodof claim 1, wherein the metabolite plasma concentration reaches a peakvalue of less than about 5 ng/ml.
 17. The method of claim 1, wherein theadverse drug experience is an experience selected from the groupconsisting of: gastrointestinal/genitourinary, nervous system,cardiovascular, dermatological, and opthalmic experiences, or acombination thereof.
 18. An article of manufacture for transmucosalapplication comprising: a transmucosal formulation including acomposition of oxybutynin and optionally including a permeationenhancer, wherein the composition provides, upon administration to asubject, a plasma AUC ratio of oxybutynin to an oxybutynin metabolitefrom about 0.5:1 to about 5:1, and wherein said transmucosal formulationminimizes an anticholinergic or antimuscarinic adverse drug experienceassociated with the administration of oxybutynin.
 19. The article ofmanufacture of claim 18, wherein the transmucosal formulation is abuccal tablet.
 20. The article of manufacture of claim 18, wherein thetransmucosal formulation is a sublingual tablet.
 21. The article ofmanufacture of claim 18, wherein the transmucosal formulation is anadhesive film.
 22. The article of manufacture of claim 18, wherein theAUC ratio of oxybutynin to an oxybutynin metabolite is from about 1:1 toabout 5:1.
 23. The article of manufacture of claim 18, wherein the AUCratio of oxybutynin to an oxybutynin metabolite is from about 0.8:1 toabout 1.5:1.
 24. The article of manufacture of claim 18, wherein theoxybutynin in the plasma is (R)-oxybutynin, (S)-oxybutynin, or acombination thereof.
 25. The article of manufacture of claim 18, whereinthe metabolite of oxybutynin is N-desethyloxybutynin.
 26. The article ofmanufacture of claim 25, wherein the N-desethyloxybutynin is(R)-N-desethyloxybutynin, (S)-N-desethyloxybutynin or a combinationthereof.
 27. The article of manufacture of claim 24, wherein the AUCratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1.
 28. Thearticle of manufacture of claim 26, wherein the AUC ratio of(R)-N-desethyloxybutynin to (R)-oxybutynin is from about 0.4:1 to about1.6:1.
 29. The article of manufacture of claim 28, wherein the AUC ratioof (R)-N-desethyloxybutynin to (R)-oxybutynin is about 1:1.
 30. Thearticle of manufacture of claim 26, wherein the AUC ratio of(R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin is from about 0.5:1to about 1.3:1.
 31. The article of manufacture of claim 30, wherein theAUC ratio of (R)-N-desethyloxybutynin to (S)-N-desethyloxybutynin isabout 0.9:1.
 32. The article of manufacture of claim 18, wherein themetabolite plasma concentration reaches a peak plasma value of less thanabout 8 ng/ml.
 33. The article of manufacture of claim 18, wherein themetabolite plasma concentration reaches a peak value of less than about5 ng/ml.
 34. The article of manufacture of claim 18, wherein the adversedrug experience is an experience selected from the group consisting of:gastrointestinal/genitourinary, nervous system, cardiovascular,dermatological, and opthalmic experiences, or a combination thereof. 35.The method of claim 1, where the permeation enhancer is a memberselected from the group consisting essentially of: fatty acids, fattyacid esters, fatty alcohols, fatty acid esters of lactic acid orglycolic acid, glycerol triesters, glycerol diesters, glycerolmonoesters, triacetin, short chain alcohols, and mixtures thereof. 36.The method of claim 35, wherein the permeation enhancer is triacetin.37. The method of claim 1, wherein the oxybutynin is a mixture ofR-oxybutynin and S-oxybutynin.
 38. The method of claim 1, wherein theoxybutynin is R-oxybutynin.
 39. The method of claim 1, wherein theoxybutynin is S-oxybutynin.
 40. The article of manufacture of claim 18,where the permeation enhancer is a member selected from the groupconsisting essentially of: fatty acids, fatty acid esters, fattyalcohols, fatty acid esters of lactic acid or glycolic acid, glyceroltriesters, glycerol diesters, glycerol monoesters, triacetin, shortchain alcohols, and mixtures thereof.
 41. The article of manufacture ofclaim 40, wherein the permeation enhancer is triacetin.
 42. The articleof manufacture of claim 18, wherein the oxybutynin is a mixture ofR-oxybutynin and S-oxybutynin.
 43. The article of manufacture of claim18, wherein the oxybutynin is R-oxybutynin.
 44. The article ofmanufacture of claim 18, wherein the oxybutynin is S-oxybutynin.
 45. Themethod of claim 1, wherein the metabolite is N-desethyloxybutynin andthe peak plasma concentration of N-desethyloxybutynin is from about 0.5ng/ml to about 8 ng/ml.
 46. The method of claim 1, wherein themetabolite is N-desethyloxybutynin and the peak plasma concentration ofN-desethyloxybutynin is less than about 5 ng/ml.
 47. The method of claim1, wherein the metabolite is N-desethyloxybutynin and the peak plasmaconcentration of N-desethyloxybutynin is from about 1.0 ng/ml to about 3ng/ml.
 48. The method of claim 1, wherein the metabolite isN-desethyloxybutynin and the N-desethyloxybutynin AUC does not exceedthe oxybutynin AUC by more than a ratio of about 2:1.
 49. The method ofclaim 1, wherein the metabolite is N-desethyloxybutynin and the peakplasma concentration of N-desethyloxybutynin is about 3 ng/ml.
 50. Themethod of claim 1, wherein the metabolite is N-desethyloxybutynin andthe AUC ratio of oxybutynin to N-desethyloxybutynin is from about 0.5:1to about 4:1.
 51. The method of claim 1, wherein the metabolite isN-desethyloxybutynin and the AUC ratio of oxybutynin toN-desethyloxybutynin is from about 1:1 to 5:1.
 52. The method of claim1, wherein the metabolite is N-desethyloxybutynin and the AUC ratio ofoxybutynin to N-desethyloxybutynin is from about 0.8:1 to about 2.5:1.53. The method of claim 6, wherein the metabolite isN-desethyloxybutynin.
 54. The method of claim 1, wherein oxybutyninplasma concentrations are below about 2.0 ng/ml at about 6 hours afteradministration.
 55. The method of claim 1, wherein the metabolite isN-desethyloxybutynin and the N-desethyloxybutynin plasma concentrationsare below about 2.0 ng/ml at about 6 hours after administration.
 56. Themethod of claim 1, wherein the metabolite is N-desethyloxybutynin andoxybutynin and N-desethyloxybutynin plasma concentrations are belowabout 8 ng/ml at about 24 hours after initial administration.
 57. Themethod of claim 1, wherein the metabolite is N-desethyloxybutynin and atsteady state, the oxybutynin and N-desethyloxybutynin plasmaconcentrations are below about 8 ng/ml for the duration ofadministration.
 58. The method of claim 57, wherein the duration ofadministration is from about 24 to about 96 hours.
 59. The method ofclaim 1, wherein the transmucosal formulation is administered for aduration of from about 24 to about 96 hours.
 60. The method of claim 13,wherein peak plasma concentration and AUC for (R)-N-desethyloxybutyninare about equal to or less than the peak plasma concentration and AUCfor (S)-N-desethyloxybutynin.
 61. The method of claim 11, wherein peakplasma concentration and AUC for (R)-oxybutynin are approximately equalto the peak plasma concentration and AUC for (R)-N-desethyloxybutynin.62. The method of claim 9, wherein (R)-N-desethyloxybutynin has a peakplasma concentration of less than about 4 ng/mL.
 63. The method of claim9, wherein (R)-N-desethyloxybutynin has a peak plasma concentrationbetween about 0.25 ng/ml to about 4 ng/ml.
 64. The method of claim 9,wherein (R)-N-desethyloxybutynin has a peak plasma concentration ofabout 1.5 ng/ml.
 65. The method of claim 9, wherein(R)-N-desethyloxybutynin has an AUC of about 100 ng×hr/ml.
 66. Themethod of claim 9, wherein (R)-N-desethyloxybutynin has an AUC of fromabout 30 ng×hr/ml to about 170 ng×hr/ml.
 67. The method of claim 9,wherein (R)-N-desethyloxybutynin plasma concentration is below about 1ng/ml at about 6 hours after initiation of administration.
 68. Themethod of claim 9, wherein (R)-N-desethyloxybutynin plasma concentrationis below about 2 ng/ml at about 24 hours after initiation ofadministration.